The present invention relates to mass spectrometers.
In many tandem mass spectrometers ions are fragmented in a collision or fragmentation cell. A known fragmentation cell comprises a multipole (e.g. a quadrupole or hexapole) rod set wherein adjacent rods are connected to opposite phases of an RF voltage supply. The quadrupole or hexapole collision cell is housed in a cylindrical housing which is open at an upstream end and at a downstream end to allow ions to enter and exit the collision cell. The housing includes a gas inlet port through which a collision or buffer gas, typically nitrogen or argon, is introduced into the collision cell. The collision cell is maintained at a pressure of 10xe2x88x923-10xe2x88x922 mbar.
Ions entering the collision cell are arranged to be sufficiently energetic so that when they collide with the collision or buffer gas at least some of the ions will fragment into daughter or fragment ions by means of Collisional Induced Dissociation/Decomposition (xe2x80x9cCIDxe2x80x9d). Ions in the collision cell will also become thermalised after they have undergone a few collisions i.e. their kinetic energy will be considerably reduced, and this leads to greater radial confinement of the ions in the presence of the RF electric field. In order to ensure that ions are sufficiently energetic so as to fragment when entering the collision cell, the collision cell is typically maintained at a DC potential which is offset from that of the ion source by approximately xe2x88x9230V DC or more (for positive ions). Once ions have fragmented and have been thermalised within the collision cell, their low kinetic energy is such that they will tend to remain within the collision cell. In practice, ions are observed to exit the collision cell after a relatively long period of time, and this is believed to be due to the effects of diffusion and the repulsive effect of further ions being admitted into the collision cell.
Accordingly, one of the problems associated with the known collision cell is that ions tend to have a relatively long residence time within the collision cell. This is problematic for certain types of mass spectrometry methods since it is necessary to wait until ions have exited the collision cell before further ions are admitted into it. For example, in MS/MS (i.e. fragmentation) modes of operation if a quadrupole mass filter Q1 (MS1) upstream of a collision cell Q2 is scanned rapidly compared to the typical empty time (xcx9c30 ms) of ions to exit the collision cell Q2, then the peaks in the resulting parent ion scanning mass spectrum will suffer from peak tailing towards higher mass and thus the resulting mass spectrum will suffer from relatively poor resolution. An example of this is shown in FIG. 16(a).
Similarly, in Multiple Reaction Monitoring (MRM) experiments the upstream quadrupole mass filter Q1 (MS1) is switched rapidly to cyclically transmit a number of parent ions (e.g. P1, P2 . . . Pn) in a multiplexed manner, and the long empty times of ions to exit the collision cell Q2 may result in cross-talk between the various channels.
Long empty times of ions to exit the collision cell Q2 is also problematic when the mass spectrometer is being used in on-line chromatography applications since each peak only elutes over a short period of time and the mass spectrometer will have to acquire data very rapidly if a full parent (precursor) ion spectrum is desired.
It is therefore desired to provide an improved collision or fragmentation cell for use in a mass spectrometer which does not suffer from some or all of the problems discussed above.
According to a first aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein at least some of the electrodes are connected to both a DC and an AC or RF voltage supply and wherein an axial DC voltage gradient or difference is maintained in use along at least a portion of the length of the fragmentation cell.
The preferred collision or fragmentation cell differs from a conventional multipole collision cell in that instead of comprising four or six elongated rod electrodes, the fragmentation cell comprises a number (e.g. typically  greater than 100) of ring, annular or plate like electrodes having apertures, preferably circular, through which ions are transmitted. Furthermore, an axial DC voltage gradient is preferably maintained across at least a portion of the length of the fragmentation cell, preferably the whole length of the fragmentation cell.
The fragmentation cell according to the preferred embodiment is capable of being emptied of and filled with ions much faster than a conventional collision cell. Mass spectra obtained using the preferred fragmentation cell exhibit improved resolution and greater sensitivity.
The fragmentation cell may comprise 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, or  greater than 150 electrodes. The fragmentation cell may have a length  less than 5 cm, 5-10 cm, 10-15 cm, 15-20 cm, 20-25 cm, 25-30 cm, or  greater than 30 cm. Preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the electrodes are connected to both a DC and an AC or RF voltage supply. According to a one embodiment, an axial DC voltage difference of approximately 3V may be maintained along the whole length of the fragmentation cell (i.e. for positive ions, electrodes at the downstream end of the fragmentation cell are maintained at a DC voltage approximately 3V below electrodes at the upstream end of the fragmentation cell). In other embodiments the axial DC voltage difference maintained along at least a portion, preferably the whole length, of the fragmentation cell is 0.1-0.5 V, 0.5-1.0 V, 1.0-1.5 V, 1.5-2.0 V, 2.0-2.5 V, 2.5-3.0 V, 3.0-3.5 V, 3.5-4.0 V, 4.0-4.5 V, 4.5-5.0 V, 5.0-5.5 V, 5.5-6.0 V, 6.0-6.5 V, 6.5-7.0 V, 7.0-7.5 V, 7.5-8.0 V, 8.0-8.5 V, 8.5-9.0 V, 9.0-9.5 V, 9.5-10.0 V or  greater than 10V.
In terms of V/cm, the axial DC voltage gradient maintained along at least a portion of the fragmentation cell, and preferably along the whole length of the collision cell, may be 0.01-0.05 V/cm, 0.05-0.10 V/cm, 0.10-0.15 V/cm, 0.15-0.20 V/cm, 0.20-0.25 V/cm, 0.25-0.30 V/cm, 0.30-0.35 V/cm, 0.35-0.40 V/cm, 0.40-0.45 V/cm, 0.45-0.50 V/cm, 0.50-0.60 V/cm, 0.60-0.70 V/cm, 0.70-0.80 V/cm, 0.80-0.90 V/cm, 0.90-1.0 V/cm, 1.0-1.5 V/cm, 1.5-2.0 V/cm, 2.0-2.5 V/cm, 2.5-3.0 V/cm or  greater than 3.0 V/cm.
The voltage gradient may be a linear voltage gradient, or the voltage gradient may have a stepped or curved stepped profile similar to that shown in FIG. 4. The term xe2x80x9cvoltage gradientxe2x80x9d should be construed broadly to cover embodiments wherein the DC voltage offset of electrodes along the length of the fragmentation cell relative to the DC potential of the ion source varies at different points along the length of the fragmentation cell. This term should not, however, be construed to include arrangements wherein all the electrodes forming the fragmentation cell are maintained at substantially the same DC potential.
According to the preferred embodiment, the electrodes forming the fragmentation cell are supplied with an AC or RF voltage which can be considered to be superimposed upon the DC potential supplied to the electrodes. Preferably, adjacent electrodes are connected to opposite phases of an AC or RF supply but according to other less preferred embodiments adjacent electrodes may be connected to different phases of the AC or RF supply i.e. voltage supplies having more than two phases are contemplated. Furthermore, although according to the preferred embodiment the AC or RF voltage supplied to the electrodes has a sinusoidal waveform (with a frequency 0.1-3.0 MHz, preferably 1.75 MHz), non-sinusoidal waveforms including square waves may be supplied to the electrodes.
According to a particularly preferred embodiment, the fragmentation cell may comprise a plurality of segments. In one embodiment fifteen segments are provided. Each segment comprises a plurality of electrodes, with preferably either eight or ten electrodes per segment. Each electrode has an aperture through which ions are transmitted. The diameter of the apertures of at least 50% of the electrodes forming the fragmentation cell is preferably xe2x89xa610 mm, xe2x89xa69 mm, xe2x89xa68 mm, xe2x89xa67 mm, xe2x89xa66 mm, xe2x89xa65 mm, xe2x89xa64 mm, xe2x89xa63 mm, xe2x89xa62 mm, or xe2x89xa61 mm. The thickness of at least 50% of the electrodes forming the fragmentation cell is preferably xe2x89xa63 mm, xe2x89xa62.5 mm, xe2x89xa62.0 mm, xe2x89xa61.5 mm, xe2x89xa61.0 mm, or xe2x89xa60.5 mm. Preferably, at least 50%, 60%, 70%, 80%, 90% or 95% of the electrodes forming the fragmentation cell have apertures which are substantially the same size or area. All the electrodes in a particular segment are preferably maintained at substantially the same DC potential, but adjacent electrodes in a segment are preferably supplied with different or opposite phases of an AC or RF voltage.
In an embodiment, ions may be trapped within the fragmentation cell in a mode of operation. Embodiments are contemplated wherein ions may be trapped in a downstream portion of the fragmentation cell whilst ions may be continually admitted into an upstream portion of the fragmentation cell. V-shaped axial DC potential profiles may be used to accelerate and trap ions within the collision cell.
The fragmentation cell is preferably maintained, in use, at a pressure  greater than 1.0xc3x9710xe2x88x923 mbar,  greater than 5.0xc3x9710xe2x88x923 mbar,  greater than 1.0xc3x9710xe2x88x922 mbar 10xe2x88x923-10xe2x88x922 mbar, or 10xe2x88x924-10xe2x88x921 mbar.
The mass spectrometer preferably comprises a continuous ion source, further preferably an atmospheric pressure ion source, although other ion sources are contemplated. Electrospray (xe2x80x9cESIxe2x80x9d), Atmospheric Pressure Chemical Ionisation (xe2x80x9cAPCIxe2x80x9d), Atmospheric Pressure Photo Ionisation (xe2x80x9cAPPIxe2x80x9d), Matrix Assisted Laser Desorption Ionisation (xe2x80x9cMALDIxe2x80x9d), non-matrix assisted Laser Desorption Ionisation, Inductively Coupled Plasma (xe2x80x9cICPxe2x80x9d), Electron Impact (xe2x80x9cEIxe2x80x9d) and Chemical Ionisation (xe2x80x9cCIxe2x80x9d) ion sources may be provided.
The fragmentation cell preferably comprises a housing having an upstream opening for allowing ions to enter the fragmentation cell and a downstream opening for allowing ions to exit the fragmentation cell.
According to a second aspect of the present invention, there is provided a mass spectrometer comprising: an ion source; one or more ion guides; a first quadrupole mass filter; a fragmentation cell for fragmenting ions, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein at least some of the electrodes are connected to both a DC and an AC or RF voltage supply and wherein an axial DC voltage gradient or difference is maintained in use along at least a portion of the length of the fragmentation cell; a second quadrupole mass filter; and a detector.
According to a third aspect of the present invention, there is provided a mass spectrometer comprising: an ion source; one or more ion guides; a quadrupole mass filter; a fragmentation cell for fragmenting ions, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein at least some of the electrodes are connected to both a DC and an AC or RF voltage supply and wherein an axial DC voltage gradient or difference is maintained in use along at least a portion of the length of the fragmentation cell; and a time of flight mass analyser.
Preferably, the fragmentation cell comprises a plurality of segments, each segment comprising a plurality of electrodes having apertures through which ions are transmitted and wherein all the electrodes in a segment are maintained at substantially the same DC potential and wherein adjacent electrodes are supplied with different phases of an AC or RF voltage.
The one or more ion guides may comprise one or more AC or RF only ion tunnel ion guides (wherein at least 90% of the electrodes have apertures which are substantially the same size) and/or one or more hexapole ion guides.
According to a fourth aspect of the present invention, there is provided a mass spectrometer comprising: a first mass filter/analyser; a fragmentation cell for fragmenting ions, the fragmentation cell being arranged downstream of the first mass filter/analyser and comprising at least 20 electrodes having apertures through which ions are transmitted in use, wherein at least 75% of the electrodes are connected to both a DC and an AC or RF voltage supply and wherein a non-zero axial DC voltage gradient or difference is maintained in use along at least 75% of the length of the fragmentation cell; and a second mass filter/analyser arranged downstream of the fragmentation cell.
Preferably, the first mass filter/analyser comprises a quadruople mass filter/analyser and the second mass filter comprises a quadrupole mass filter/analyser or a time of flight mass analyser.
According to a fifth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell comprising xe2x89xa710 ring or plate electrodes having substantially similar internal apertures between 2-10 mm in diameter arranged in a housing having a buffer gas inlet port, wherein a buffer gas is introduced in use into the fragmentation cell at a pressure of 10xe2x88x924-10xe2x88x921 mbar and wherein a DC potential gradient or difference is maintained, in use, along the length of the fragmentation cell.
Preferably, the mass spectrometer further comprises an ion source and ion optics upstream of the fragmentation cell, wherein the ion source and/or the ion optics are maintained at potentials such that at least some of the ions entering the fragmentation cell have, in use, an energy xe2x89xa710 eV for a singly charged ion such that they are caused to fragment.
According to a sixth aspect of the present invention, there is provided a mass spectrometer comprising: an ion source; a fragmentation cell for fragmenting ions, the fragmentation cell comprising at least ten plate-like electrodes arranged substantially perpendicular to the longitudinal axis of the fragmentation cell, each electrode having an aperture therein through which ions are transmitted in use, the fragmentation cell being supplied in use with a collision gas at a pressure xe2x89xa710xe2x88x923 mbar, wherein adjacent electrodes are connected to different phases of an AC or RF voltage supply and a DC potential gradient xe2x89xa70.01 V/cm is maintained over at least 20% of the length of the fragmentation cell; and ion optics arranged between the ion source and the fragmentation cell; wherein in a mode of operation the ion source, ion optics and fragmentation cell are maintained at potentials such that singly charged ions are caused to have an energy xe2x89xa710 eV upon entering the fragmentation cell so that at least some of the ions fragment into daughter ions.
According to a seventh aspect of the present invention, there is provided a mass spectrometer comprising: a collision or fragmentation cell comprising at least three segments, each segment comprising at least four electrodes having substantially similar sized apertures through which ions are transmitted in use; wherein in a mode of operation: electrodes in a first segment are maintained at substantially the same first DC potential but adjacent electrodes are supplied with different phases of an AC or RF voltage supply; electrodes in a second segment are maintained at substantially the same second DC potential but adjacent electrodes are supplied with different phases of an AC or RF voltage supply; electrodes in a third segment are maintained at substantially the same third DC potential but adjacent electrodes are supplied with different phases of an AC or RF voltage supply; wherein the first, second and third DC potentials are all different.
According to an eighth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein at least some of the electrodes are connected to an AC or RF voltage supply.
Preferably, at least some of the electrodes are also connected to a DC voltage supply and wherein an axial DC voltage gradient or difference is maintained in use along at least a portion of the length of the fragmentation cell.
According to a ninth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein in a mode of operation at least a portion of the fragmentation cell is maintained at a DC potential so as to prevent ions from exiting the fragmentation cell.
According to a tenth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein the empty time taken for ions to exit the fragmentation cell is selected from the group comprising: (i) xe2x89xa60.5 ms; (ii) xe2x89xa61.0 ms; (iii) xe2x89xa65 ms; (iv) xe2x89xa610 ms; (v) xe2x89xa620 ms; (vi) 0.01-0.5 ms; (vii) 0.5-1 ms; (viii) 1-5 ms; (ix) 5-10 ms; and (x) 10-20 ms.
According to an eleventh aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, and wherein in a mode of operation trapping DC voltages are supplied to some of the electrodes so that ions are confined in two or more axial DC potential wells.
According to a twelfth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, and wherein in a mode of operation a V-shaped, sinusoidal, curved, stepped or linear axial DC potential profile is maintained along at least a portion, preferably at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the length of the fragmentation cell.
According to a thirteenth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, and wherein in a mode of operation an upstream portion of the fragmentation cell continues to receive ions into the fragmentation cell whilst a downstream portion of the fragmentation cell separated from the upstream portion by a potential barrier stores and periodically releases ions.
Preferably, the upstream portion of the fragmentation cell has a length which is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total length of the fragmentation cell. Preferably, the downstream portion of the fragmentation cell has a length which is less than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total length of the fragmentation cell. Further preferably, the downstream portion of the fragmentation cell is shorter than the upstream portion of the fragmentation cell.
According to a fourteenth aspect of the present invention, there is provided a mass spectrometer comprising: a fragmentation cell in which ions are fragmented in use, said fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, and wherein in a mode of operation an AC or RF voltage is applied to at least some of said electrodes and the peak amplitude of said AC or RF voltage is varied.
Preferably, the peak amplitude of the AC or RF voltage is increased in time.
Preferably, when ions having a mass to charge ratio  less than 500,  less than 400,  less than 300,  less than 200,  less than 100, or  less than 50 are admitted into the fragmentation cell the peak amplitude of the AC or RF voltage is xe2x89xa7200 VPp, xe2x89xa7150 VPp, xe2x89xa7100 VPp, or xe2x89xa760 VPp.
Preferably, when ions having a mass to charge ratio  greater than 500,  greater than 600,  greater than 700,  greater than 800,  greater than 900, or  greater than 1000 are admitted into the fragmentation cell the peak amplitude of the AC or RF voltage is xe2x89xa7100 VPp, xe2x89xa7150 VPp, xe2x89xa7200 VPp, xe2x89xa7250 VPp, or xe2x89xa7300 VPp.
According to a fifteenth aspect of the present invention, there is provided a method of mass spectrometry, comprising: fragmenting ions in a fragmentation cell, the fragmentation cell comprising a plurality of electrodes having apertures through which ions are transmitted in use, wherein at least some of the electrodes are connected to both a DC and an AC or RF voltage supply and wherein an axial DC voltage gradient or difference is maintained in use along at least a portion of the length of the fragmentation cell.